tbuckley/cabot-search huggingface dataset:
Abstract 9597: One Drop Digital App and Coaching Improves Lifestyle Risks, Glycemic Control and Psychological Well-Being in People With Hypertension and Type 2 Diabetes
Authors: Lindsay E Sears, Dan Goldner, Harpreet Nagra, PhD, Brian Huddleston, Ashley Hirsch, Chandra Y Osborn, Jeff Dachis
Journal: Circulation (2021)

Background: Mobile health interventions for reducing CVD risk have mixed effectiveness. One Drop’s (OD) digital solution integrates a mobile application, in-app coaching and connected devices (glucometer, blood pressure cuff, scale) to support management of pre-diabetes, diabetes and hypertension. Secondary analyses of the Fit-One pragmatic RCT evaluated effects of OD on lifestyle, clinical and psychological outcomes for people with CVD risks of hypertension and type 2 diabetes (T2D). Methods: Fit-One enrolled adults with diabetes (HbA1c &amp;gt 7%) who had never used OD. Subjects were randomized to get OD only, OD with fitness tracker or a waitlist control group. Present analyses compared just OD only to control subjects with T2D and hypertension. At baseline and 3-months, subjects completed validated measures of general self-rated health (GSRH), eating behavior problems (PDQ), vigorous, moderate and walking activity (mins in past week), life satisfaction, depression (PHQ-2) and HbA1c tests. MI corrected for missingness. Intent-to-treat (ITT) and per protocol (PP) analyses used ANCOVA and logistic models controlling for baseline outcomes. Results: Participants (N=115) tended to be female, white, non-hispanic and had health insurance. Treatment (N = 58) and control (N = 57) did not differ in baseline demographics or outcomes. In ITT models, main effects for general health, moderate activity, life satisfaction and depression and significant interactions for eating behavior problems, walking and A1c indicated benefit to the OD group (p &amp;lt .05). Vigorous activity was not significant. PP models replicated findings yet moderate activity was not significant (p = .07), likely due to lower power. Within the OD group, moderate activity increased (p = .01). Conclusions: Over 3 months, OD users realized 15% higher health ratings (from 2.2); 10% fewer eating behavior problems (from 4.1); 105% more walking, 132% more moderate activity and 55% more vigorous activity (from 77, 67, 35 mins/wk); .72% absolute reduction in A1c and 4.7 times lower risk of depression vs. control (all PP). RCT results support the effectiveness of One Drop’s digital solution in improving lifestyle risks, glycemic control and psychological well-being in people at risk for CVD.
Abstract 13554: High-Throughput Investigation of Human Genes and Variants Affecting LDL Cholesterol Uptake
Authors: Marisa C Hamilton, James D Fife, Minsun Cha, Christopher A Cassa, Richard I Sherwood
Journal: Circulation (2021)

Introduction: Genetic differences in cholesterol metabolism are major contributors to the risk of coronary artery disease (CAD), which is the leading cause of death in the USA. Genome-wide association screens have identified over 300 independent genomic loci where genetic variation is associated with serum LDL cholesterol (LDL-C) levels. While several of these loci are important drug targets, for the vast majority of loci, it is unknown which exact genetic variants, genes and cellular pathways are impacted by these variants. Hypothesis: We hypothesize that combining high-throughput CRISPR-Cas9 screening, gene clustering and network analysis, and human genetic biobank cohort analysis will increase our power to reveal the genetic basis behind human variation in cholesterol levels. Methods: We have devised sensitive high-throughput CRISPR-Cas9-based screens to gain insight into the genetic mechanisms that impact cellular cholesterol metabolism. Results: Through a combination of CRISPR-Cas9-nuclease and CRISPR base editing screens, we have identified hundreds of human genes and GWAS-associated variants that influence cellular LDL-C uptake in liver cells. We have developed experimental and computational methods to group these genes into biological pathways, uncovering previously unappreciated cellular mechanisms driving variation in LDL-C uptake. We have connected these novel LDL-C uptake-altering genes and pathways to serum LDL-C levels by analyzing rare coding variant burden from a UK Biobank exome sequencing cohort, identifying functional gene modules for which damaging coding variants in the population have significant effects LDL-C levels. Finally, we have identified GWAS-associated non-coding variants that alter LDL-C uptake through modulating expression of previously unappreciated cholesterol-related genes. Conclusions: Through high-throughput CRISPR screening followed by mechanistic follow-up, we have made progress in dissecting the non-coding loci, genes, and pathways that underlie variation in human cellular cholesterol uptake.
Abstract 9601: Sarcolipin Reduction Prevents Mitochondrial Dysfunction in Dystrophic Myocardium
Authors: Satvik Mareedu, Nadezhda Fefelova, Lai-hua Xie, Gopal J Babu
Journal: Circulation (2021)

Rationale &amp; Hypothesis: Sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) is abnormally high and enriched in the mitochondrial associated membrane (MAM) fractions of dystrophic hearts. We, therefore, hypothesized that in the dystrophic cardiomyocytes, SLN upregulation causes abnormal elevation of intracellular Ca 2+ (Ca 2+ i ) including Ca 2+ mishandling in the MAM region, resulting in sustained elevation of mitochondrial Ca 2+ (Ca 2+ m ), which in turn affects mitochondrial structure and function. Approach: We chose dystrophin mutant and utrophin deficient, mdx:utr -/- mice for our studies and generated SLN haploinsufficient mdx:utr -/- (mdx:utr -/- :sln +/- ) mice. Single-cell Ca 2+ transients and Ca 2+ m efflux were measured in isolated cardiomyocytes (CM's) to determine Ca 2+ i handling and Ca 2+ m content, respectively. Mitochondrial membrane potential was assessed with membrane-permeant dyes in isolated CM's followed by confocal imaging. Mitochondrial respiration was measured using Complex activity assays and Seahorse metabolic profiling in ventricular tissue lysates and isolated mitochondria respectively. Mitochondrial structure, number, and area were evaluated using electron micrographs (EM). Results: Heterozygous deletion of the SLN gene normalized SLN expression and improved Ca 2+ i cycling and prevented Ca 2+ m overload in dystrophic CM's. Furthermore, reducing SLN expression prevents loss of membrane potential and improves mitochondrial respiration in the dystrophic cardiac myocytes. TEM analyses of the dystrophic heart revealed significant cristae loss in the mitochondria globally as well as in the MAM-associated mitochondria. On the other hand, the reduction in SLN expression prevents these changes. Conclusions: In conclusion, reduction in SLN expression preserves the SR-mitochondrial interface and restores the mitochondrial function by mitigating the Ca 2+ overload, membrane potential loss, and structural damage. These changes improve cardiac function and prevent the development of cardiomyopathy in mdx:utr -/- mice. Our findings suggest that SLN reduction could be a potential therapeutic strategy for the treatment of Duchenne muscular dystrophy and associated cardiomyopathy.
Abstract 12996: Prospective Study of Patient Reported Outcomes and Costs Associated With Same Day Discharge and Vascular Closure for Atrial Fibrillation Ablation
Authors: Benjamin A Steinberg, Shannon Woolley, HAOJIA LI, Chase Maires, Christopher Groh, Leenhapong Navaravong, Ravi Ranjan, Yue Zhang, T. J Bunch
Journal: Circulation (2021)

Introduction: Overnight stay after ablation for atrial fibrillation (AF) is standard practice, in part driven by the need for bedrest required to maintain hemostasis. We aimed to measure patient reported outcomes (PROs) and costs associated with same day discharge (SDD) for AF ablation and vascular closure device implantation in clinical practice. Methods: PROs were measured in 50 patients prospectively enrolled prior to AF ablation with post procedure treatment by complete vascular device closure (n=25) versus compression hemostasis (n=25). Health-system costs for SDD patients receiving vascular device closure were compared to matched controls with one-night stays who did not receive closure devices. Results: Patients receiving vascular device closure for AF ablation had mean age 65, 17% female, with mean CHA 2 DS 2 -VASc score 3. Mean number of venous sheaths was higher among patients receiving vascular device closure (3.8 vs. 3.1, p&lt;0.001), and there was 1 case of re-bleeding in a patient receiving vascular closure device (no other vascular complications). Same-day discharge rates (76% vs. 8.3%, p&lt;0.001), patient satisfaction with bedrest time (8.5 vs. 6, p=0.004) and with pain (8 vs. 5.1, p=0.009) were significantly higher among patients receiving vascular closure. For health-system costs, patients with vascular closure the mean age was 66, 36% were female, with a mean CHA 2 DS 2 -VASc score of 2 (p=NS for each vs. matched controls). SDD with vascular closure was associated with significantly lower facility, pharmacy, and disposable costs, but higher implant costs ( Table ). Overall costs for ablation were not different based on conservative estimates for overnight stay costs. Conclusions: Vascular closure for AF ablation improves patient experience in routine clinical care. Use of vascular closure and SDD after AF ablation reduces several components of health system costs, without an overall increase, and may be cost-saving in comparative healthcare systems.
Abstract 13534: Plasma Apolipoprotein C3 is Negatively Associated With High Lipoprotein(a) Plasma Levels in Healthy Volunteers
Authors: Anastasiya Matveyenko, Nelsa Matienzo, Tiffany Thomas, Sekhar Ramakrishnan, Heather Seid, Henry N Ginsberg, Gissette Reyes-soffer
Journal: Circulation (2021)

Introduction: ApoliproteinC3 (apoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. A recent study reported the presence of apoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an apoB100 containing lipoprotein with apo(a) covalently bound and is a causal factor of ASCVD. Our goal was to investigate relationships between apoC3 and Lp(a) in a healthy population. Methods: We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Irving Medical Center. Subjects were 18 - 75 years old, and 44% were female. Twenty were Black, 9 Hispanic, 8 White, and 2 mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by an automatic analyzer. Plasma apoC3, apoB100 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody and Western blots were performed. Results: We did not find an association between plasma Lp(a) and apoC3 levels. In a sub-group analysis of participants (N=15), with Lp(a) levels &gt;100nmol/L, we found a significant negative association between apoC3 and Lp(a) plasma concentrations (R = -0.58, p=0.018). Based on the Western blots and ELISA analysis, we see an interaction between Lp(a) (apo(a) and apoB100 intact) and apoC3. There seem to be some differences in the Lp(a) and apoC3 interaction based on Lp(a) plasma concentration. Conclusion and Future Direction: In healthy subjects, there is no association of apoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed an association with apoC3 plasma levels. Our small data set suggests possible distinct roles for apoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts and examining lipid composition in the isolated particles.
Abstract 14026: Systemic Delivery of SOD2 mRNA to Experimental Abdominal Aortic Aneurysm Mitigates Expansion
Authors: Huimin Yan, Ying Hu, Antonina Akk, Hua Pan, Samuel Wickline, Christine Pham
Journal: Circulation (2021)

Rationale: Oxidative stress and the overproduction of reactive oxygen species are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest. Yet, despite promising experimental studies, clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient levels locally at the site of AAA. Herein, we explore a nanoparticle (NP)-based approach for the systemic delivery of antioxidants. Methods and Results: We employ a peptide-based NP that allows efficient in vivo delivery of mRNA to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The SOD2 mRNA sequence containing the appropriate endcaps, poly-A tail, and base modifications (~1,000 nt) to enhance translation was mixed with p5RHH (an amphipathic peptide capable of efficiently delivering nucleic acids in vivo ) at a ratio of 3,200:1 (peptide:mRNA) to form a self-assembled NP of ~50-55 nm in diameter. The NP was further stabilized by a coating of hyaluronic acid (HA), which binds to CD44 expressed on a wide range of cells, enhancing targeting and uptake. Delivery of SOD2 mRNA suppresses expansion of small AAA. Mitigation of AAA following SOD2 mRNA delivery was accompanied by enhanced SOD2 protein expression in aortic wall tissue, decreased inducible nitric oxide synthase expression, lower nitric oxide production and cell death. Conclusions: The results will serve as proof-of-concept that the delivery of mRNA using the p5RHH-based NP holds promise to overcome challenges associated with systemic delivery of antioxidants in AAA medical management. Figure 1. Mice were perfused with elastase and administered NP iv (1 μg mRNA) on days 5, 8, 11. (A) Increase in (AD), measured on day 14 as increase in mm or %. Day 14 aortic sections (n = 5-6 aortas) were stained for SOD2 (red) and nitrotyrosine (green, NO) and expressed as relative ratios. * P &lt;0.05, ** P &lt;0.01, *** P &lt;0.01.
Abstract 12875: The Impact of Social Determinants of Health and Race Disparities in Heart Transplant Long-Term Survival
Authors: Ahmed Alnajar, Eugene H Blackstone, Isildinha M Reis, Tawseef A Dar, Connor Callahan, Abbas Rana, Ana M Palacio, J Sunil Rao
Journal: Circulation (2021)

Introduction: : Patients of color have a higher early mortality risk after heart transplantation than White recipients, even after taking differences in comorbidities into account. We aimed to assess long-term heart transplantation success based on patient's social determinants of health. Hypothesis: Socio-demographic indices that identify patients of socioeconomic (SES) disadvantage can predict poorer heart graft survival. Methods: We studied 34,584 adult heart transplant recipients from 2004 to 2020 using OPTN database. Established and modern SES indices—including the Agency for Healthcare Research and Quality index (AHRQ), the Area Deprivation Index (ADI), Social Vulnerability Index (SVI), Social Deprivation Index (SDI), and Crime Risk index—were evaluated. We performed survival analysis using Kaplan-Meier, univariable and multivariable Cox regression. Penalized LASSO algorithm was used during model development for variable selection among large number of patient characteristics (e.g., recipient and donor biological factors and comorbidities) related to heart transplantation. Results: On average, the worst level of disadvantage across different SES indices resulted in a 20% increased risk of graft failure (Table 1A). After accounting for the recipient and donor biological factors and comorbidities, the recipients' indices remained statistically significant. Non-white patients (HR:1.10, p&lt;0.001), no private insurance (HR:1.19,p&lt;0.001), and education less than college (HR:1.09,p=0.006) were also statistically significant . Donor SES indices had numerically higher hazard ratios, without statistical significance (Table 1B). Conclusions: Recipients access to health care and nonadherence may stem from low health literacy, limited social support, and financial burden. Further efforts should be taken to counsel patients with socioeconomic disadvantages to improve heart transplant outcomes.
Abstract 9742: Conservation of Mir Direct Cardiac Reprogramming Across Several Mammalian Species
Authors: Syeda Baksh, Richard E Pratt, Victor J Dzau, Conrad Hodgkinson
Journal: Circulation (2021)

There is considerable interest in regenerating the injured heart by reprogramming resident fibroblasts into new functional cardiomyocytes. Cardiac reprogramming has been achieved via transcription factors or miRNAs. Transcription factor combinations appear to be species-specific as evidenced by the fact that combinations of transcription factors which are effective for the reprogramming of mouse fibroblasts, are ineffective in pigs and humans. It is unknown if miRNA based cardiac reprogramming suffers from the same limitation. We have previously demonstrated that mouse cardiac fibroblasts(mCFs) can be directly converted into cardiomyocytes both in vitro and in vivo via a combination of four microRNAs (miR-1, miR-133a, miR-208a and miR-499) termed “miR combo.” To test species-specificity, miR combo was transfected into cardiac fibroblasts isolated from the left ventricle of adult sheep, dogs, pigs and humans. Reprogramming was determined by qPCR and RNA-seq. In contrast to transcription factor based approaches, miR combo effectively reprogrammed fibroblasts from all of the tested mammalian species. Marked upregulation of cardiac developmental, sarcomere, and cardiac ion channel genes was observed (N=3-5, P&lt;0.001).Concomitant with up-regulation of cardiomyocyte-specific signatures, fibroblast-specific genes were down-regulated (N=3-5, P&lt;0.001). Moreover, we also observed marked downregulation of genes that are associated with neuronal, skeletal muscle and endothelial cells (N=3-5, P&lt;0.001). Importantly, we also found that miR comb otransfection induced dog, pig and human cardiac fibroblasts to develop into cardiomyocyte-like cells (N=3, P&lt;0.05). In conclusion, we have demonstrated that in contrast to transcription factor based approaches, miR combo effectively reprograms mammlian cardiac fibroblasts into cardiomyocyte-like cells. These findings validate the potential of miR combo as a therapeutic modality for myocardial regeneration following myocardial injury in humans.
Abstract 13570: Quantitative 3D Echocardiographic Predictors for Risk Stratification and Improved Management of Congenital Mitral Valve Disease
Authors: Nora Lang, Steven Staffa, David Zurakowski, Christopher W Baird, Sitaram Emani, Melinda H Shea, Pedro J Del Nido, Gerald R Marx
Journal: Circulation (2021)

Background: Congenital mitral valve disease (CMVD) presents major challenges regarding medical and surgical management. Three dimensional echocardiography (3DE) allows precise delineation of area tracing from cross-sectional planes for more precise measurements and outcome analysis. However, there are no available data to inform clinicians on how 3DE can help guide management. We hypothesized that quantitative 3DE measurements can provide improved risk stratification and guide management of CMVD. Methods and Results: Demographic, procedural and outcome data were obtained for all 183 children who underwent MV reconstruction for CMVD from 2002 to 2017. 92 patients had mitral stenosis (MS), 68 mitral regurgitation (MR), and 23 mixed disease (MD). 13 patients (7%) died. MD patients had higher rates of mortality, reoperation, and valve replacement. Quantitative 3DE measurements of the effective orifice area (EOA) and vena contracta regurgitant area (VCRA) were determined preoperatively and before discharge. Changes from baseline in EOA and VCRA were significant independent predictors of reoperation with excellent area under the curve (AUC) values (EOA: AUC = 0.888; VCRA: AUC = 0.962; both P&lt;0.001). As shown in Figure 1, decision analysis revealed that an increase in EOA&lt;30% for patients with MS is associated with 76% risk of reoperation (HR=11.4; 95% CI: 3.4-37.8; P&lt;0.001), whereas a decrease in VCRA &lt;40% for MR patients is associated with 93% risk of reoperation (HR=18.1; 95% CI: 2.3-142; P=0.006). Comparison of the AUC indicated that the change in EOA is a significantly stronger predictor of reoperation than change in mean gradients (MG; P=0.018; DeLong’s test). Conclusions: Reconstructive surgery for CMVD can be performed with good outcomes. 3DE EOA and VCRA aids in postoperative clinical and surgical management. Further, 3DE is more predictive of patient outcomes than 2DE measurements of MG. Thus, we now incorporate 3DE EOA and VCRA into clinical decision making.
Abstract 12251: Speckle Tracking Echocardiography Changes in Patients Who Developed Atrial Fibrillation Post Coronary Artery Bypass Grafting
Authors: Sarath Lal Mannumbeth Renjithlal, Kiro Barssoum, Medhat Chowdhury, Mohab Hassib, Abhijeeth Shankar, Suman Biswas, Ashish Kumar, Varun Victor
Journal: Circulation (2021)

Introduction: Postoperative atrial fibrillation (POAF) is seen in around 30% of patients after coronary artery bypass grafting (CABG). It is associated with increased risk for stroke, heart failure, in-hospital mortality and hospital readmission. Prediction of POAF could help institute preventive and early treatment strategies. Methods: We queried PubMed, Ovid Medline, and Cochrane databases for key words ‘atrial speckle tracking” and/or “reservoir strain” and/or “post-operative atrial fibrillation”. We included studies that included patients in normal sinus rhythm before CABG and compared reservoir strain and/or peak atrial longitudinal strain (PALS) between patients who developed POAF and those who did not. Continuous data (LA strain) was pooled as a mean difference comparing patients who developed POAF versus patients who did not. We used the inverse variance method with the Restricted Maximum likelihood estimator of Tau2, for random effect analysis. We used Q and I2 statistics to calculate the heterogeneity. Results: Six observational studies met our inclusion criteria with a total of 338 patients, of which 91 patients developed POAF. Left atrial reservoir strain was significantly reduced in patients who developed POAF as compared with those who did not develop POAF, mean difference(MD), 95% confidence interval(CI): -13.97(-15.00-12.93), I2= 53%, , P &lt;0.00001, Figure 1. Conclusions: Atrial reservoir strain was significantly reduced in patients who developed POAF as compared to those who remained in sinus rhythm. Atrial reservoir strain can be potentially used to identify patients at risk of POAF. More data is needed for further validation of this finding. .